BACKGROUND: The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized.OBJECTIVE: To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death.DESIGN: Retrospective cohort study.SETTING: National Veterans Health Administration databases linked to Medicare files.PATIENTS: Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded.MEASUREMENTS: Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions.RESULTS: Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score-matched cohort analysis; and in sensitivity analyses.LIMITATION: Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population.CONCLUSION: Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death.PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.